Hyaluronic acid, also known as hyaluronan or hyaluronate, is a biological polymer within the class of glycosaminoglycans. It is a linear polysaccharide comprising alternating glucuronic acid and N-acetyl glucosamine units. The acid form and hyaluronate salts (such as the sodium, potassium, magnesium, and calcium salts, among others, (hereinafter collectively “hyaluronic acid” or “HA”) are viscoelastic materials which can be found throughout the body as part of the extracellular matrix. HA can be isolated from natural sources, including cock combs. It varies in molecular weight from a few kDa up to several MDa (approximately from 5,000 to 20,000,000 Da in vivo). HA binds water and lubricates movable parts of the body, such as joints and muscles. It is an important component of the proteoglycans which impart resilient characteristics to articular cartilage, acts as a resilient filler in the extracellular matrix, and is a primary component of aqueous and vitreous humor and synovial fluid. It helps maintain strength and flexibility of cartilage and acts to cushion impacts. It is used medically for intra-articular injections for relief of joint pain, as a tissue filler, and as a component of various topical preparations including drops for the treatment of eye irritation.
Lubricin, or PRG4, is an endogenous human glycoprotein found in the body often in admixture or association with HA. Lubricin is a major boundary lubricant also found in various tissues and tissue surfaces, and is the chief moiety responsible for the remarkable lubrication between weight-bearing cartilage in articular joints. It has been proposed for administration by injection into the synovium to slow the worsening of arthritis symptoms. See, e.g., U.S. Pat. No. 8,026,346 and published application number US 20090104148. Pending application publication number 20130116186 discloses injection of PRG4 into asymptomatic joints at risk of developing arthritis so as to preserve and enhance joint lubrication, preserve chondrocytes and promote healthy expression of the endogenous lubricin they produce. Lubricin also has been proposed for use as a topical treatment for dry eye disease, and as a treatment for interstitial cystitis, among other uses.
Mixtures of lubricin and HA occur in the body, are known in the art, and have been proposed for A solution for injection into weight-bearing joints (e.g., U.S. Pat. No. 7,001,881, and published application numbers 20070249557 and 20080287369), for tissue lubrication (e.g., US 20110059902) and in eye drops (e.g., 20110059902), among other utilities.
Arthritis is characterized by degenerative or abnormal changes in cartilage and synovium of the joints, and ultimately bone. The most common form of arthritis is osteoarthritis (“OA”), a progressive wearing down of opposing joint surfaces accompanied by inflammation resulting in pain and swelling. It may be idiopathic, can occur following joint trauma, or may develop simply as a result of aging and joint use. Rheumatoid arthritis and other immune modulated joint disease have different etiologies but result in similar morbidity, typically in a compressed time frame.
Treatment of OA generally involves a combination of exercise or physical therapy, lifestyle modification, weight loss, intra-articular steroid injections, and analgesics. If pain becomes debilitating, joint replacement surgery is indicated to improve mobility and quality of life. There is no proven treatment to slow or reverse OA, although animal data suggests that lubricin injections, optionally in combination with HA, may slow the development of OA and reduce joint pain.
The molecular weight of synovial fluid HA molecules in healthy humans lies in the range of about 2×105 to about 107 Da; while its concentration ranges from 1 mg/mL up to about 4 mg/mL (Balazs et al., Arthritis Rheum. 10:357, 1967). The weight average molecular weight of HA in the synovial fluid of patients with arthritis such as OA and rheumatoid arthritis typically are lower than weight average molecular weight in normal synovial fluid. Also, HA fragments are thought to be able to induce an inflammatory responses. HA degradation also is thought to be associated with degradation of the lubricating and shock-absorbing effects of the synovium, and for some OA patients, intra-articular injection of HA or “viscosupplementation” is offered to restore the elastic and viscous properties of synovial fluid and thus attempt to recreate the intra-articular joint homeostasis that is disrupted in the degenerative joint. This provides an additional treatment option to address pain and can delay the need for joint replacement.
The viscoelastic properties of a hyaluronic acid preparation and its residence time in the joint cavity are influenced by its viscosity and therefore its molecular weight. Generally, the higher the molecular weight the greater the residence time and the longer the half-life in the joint. Supplementation with high molecular weight (about 2,000 kDa) HA and with cross-linked HA appear to prolong residence time, so higher molecular weight preparations are preferred, although harder to administer and more expensive. The durability of the effect is in any case limited, and to extend it the HA may be chemically modified, e.g., cross-linked or derivatized. Examples of chemical modifications which may be made to HA include any reaction of an agent with the four reactive groups of HA, namely the acetamido, carboxyl, hydroxyl, and the reducing end. U.S. Pat. No. 7,456,275 disclosed commercially successful partially cross-linked high molecular weight hyaluronic acid which is said to prolong the residence time in vivo.